Role of macrophages in Wallerian degeneration and axonal regeneration after peripheral nerve injury

Abstract

The peripheral nervous system (PNS) has remarkable regenerative abilities after injury. Successful PNS regeneration relies on both injured axons and non-neuronal cells, including Schwann cells and immune cells. Macrophages are the most notable immune cells that play key roles in PNS injury and repair. Upon peripheral nerve injury, a large number of macrophages are accumulated at the injury sites, where they not only contribute to Wallerian degeneration, but also are educated by the local microenvironment and polarized to an anti-inflammatory phenotype (M2), thus contributing to axonal regeneration. Significant progress has been made in understanding how macrophages are educated and polarized in the injured microenvironment as well as how they contribute to axonal regeneration. Following the discussion on the main properties of macrophages and their phenotypes, in this review, we will summarize the current knowledge regarding the mechanisms of macrophage infiltration after PNS injury. Moreover, we will discuss the recent findings elucidating how macrophages are polarized to M2 phenotype in the injured PNS microenvironment, as well as the role and underlying mechanisms of macrophages in peripheral nerve injury, Wallerian degeneration and regeneration. Furthermore, we will highlight the potential application by targeting macrophages in treating peripheral nerve injury and peripheral neuropathies.

Progressive Degeneration and Inhibition of Peripheral Nerve Regeneration in the SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis

“…The inflammatory response, a mechanism by which many inflammatory cells remove necrotic cellular debris, plays a crucial role in nerve injury. Macrophages are recruited and then release molecules in response to peripheral nerve injury, including interleukin-1, neurotrophic factors and transforming growth factor (TGF) [19, 28]. In our study, the expression of neurotrophic factors in mutant nerve was examined.…”

“…Wallerian degeneration involves axon and SC degeneration, macrophage recruitment, the removal of cell debris and the regeneration of the PNS [19]. SCs differentiate into myelinating or nonmyelinating SCs during PNS development [8].…”

“…Immune cells are recruited to the injured nerve to remove myelin fragments and promote axon regeneration and SC remyelination to restore motor function [19]. Mutant human SOD1, which shows a toxic gain of function phenotype, leads to abnormal changes in neurons and glia.…”

“…Inflammation is a prominent pathological feature in patients and the animal model, along with peripheral nerve injury that is characterized by macrophage recruitment and activation. An interesting question is whether myeloid macrophages that are linked to the clearance of myelin debris in the PNS participate in ALS [19]. We evaluated the timing of severe axonal degeneration and inflammatory responses in the PNS.…”

Engineering Musculoskeletal Tissue Interfaces

“…Tissue engineering aims to mimic the structure, function and composition of the native tissues in the best possible way. In order to achieve this goal, several approaches have been employed including scaffold-based and scaffold-free strategies for engineering of tissues including; bone, cartilage, tendon, ligaments, nervous tissue, and orthopedic interfaces (Freed et al, 1998;Moffat et al, 2009;Yilgor et al, 2010;Erisken et al, 2011;Chen et al, 2015). In these, either cells are directly injected to the damage site, or biomaterials are implanted without cellular content, or cells and biomaterials are combined for in vitro or in vivo applications.…”